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Progressive brain calcifications and signs in a family with the L9R mutation in the PDGFB gene.

ABSTRACT: Primary familial brain calcifications (PFBC) are a heterogeneous group of rare autosomal dominant disorders. Mutations in the PDGFB gene are the second most common cause of PFBC. A model for PDGFB-associated PFBC, hypomorphic PDGFB (ret/ret) mouse, displays impaired blood-brain barrier (BBB), progressive brain calcifications and increased flux of the oxysterol 24S-hydroxycholesterol from the brain into the circulation.(1,2) Only 8 families and 2 sporadic cases with PDGFB mutations have been identified so far, one of them a Swedish-Finnish family previously described as F13.(1,3-6) Very little is known about the natural history of PDGFB-associated PFBC. Here, we provide a comprehensive long-term follow-up of the F13 family.

SUBMITTER: Paucar M

PROVIDER: S-EPMC4937718 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Progressive brain calcifications and signs in a family with the L9R mutation in the PDGFB gene.

Paucar Martin M Almqvist Håkan H Saeed Ahmed A Bergendal Gösta G Ygge Jan J Holmin Staffan S Björkhem Ingemar I Svenningsson Per P

Neurology. Genetics 20160706 4

Primary familial brain calcifications (PFBC) are a heterogeneous group of rare autosomal dominant disorders. Mutations in the PDGFB gene are the second most common cause of PFBC. A model for PDGFB-associated PFBC, hypomorphic PDGFB (ret/ret) mouse, displays impaired blood-brain barrier (BBB), progressive brain calcifications and increased flux of the oxysterol 24S-hydroxycholesterol from the brain into the circulation.(1,2) Only 8 families and 2 sporadic cases with PDGFB mutations have been iden ...[more]

PMID: 27433546

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Project description:BackgroundIn clinical practice, calcifications seen on computed tomographic studies within the large brain arteries are often referred to as a surrogate marker for cholesterol-mediated atherosclerosis. However, limited data exist to support the association between calcification and atherosclerosis. In this study, we examined if intracranial arterial calcifications were associated with cholesterol-mediated intracranial large artery atherosclerosis (ILAA) within the arteries of the circle of Willis in an autopsy-based sample.MethodsWe carried out a cross-sectional analysis of histopathological characteristics of brain large arteries obtained from autopsy cases. Brain large arteries were examined for evidences of calcifications, which were rated as macroscopic (coalescent) and microscopic (scattered). In addition to calcification, we also obtained measurement of the arterial wall and the presence of ILAA and nonatherosclerotic arterial fibrosis. We built hierarchical models adjusted for demographic and vascular risk factors to assess the relationship between calcification and ILAA.ResultsIn univariate analysis, the presence of any arterial calcifications was associated with cerebral infarcts (29% vs. 14%, P<.01). Multivariate analysis revealed that among all calcifications, coalescent calcifications were not associated with ILAA. In contrast, scattered calcifications were associated with ILAA (P<.001), decreased lumen diameter (-1.87 +/- 0.41 mm, P≤.001), and increased luminal stenosis (0.03% +/- 0.01%, P≤.006). These findings were independent of age, sex, or other vascular risk factors.ConclusionsThis study demonstrates that coalescent calcifications in brain large arteries, although associated with morbidity, are not synonymous with cholesterol-driven ILAA. Understanding the precise pathological components of cerebrovascular disease, including nonatherosclerotic arterial calcifications, will help develop individualized therapies beyond amelioration of traditional risk factors such as hyperlipidemia.

Dataset Information

Progressive brain calcifications and signs in a family with the L9R mutation in the PDGFB gene.

Publications

Progressive brain calcifications and signs in a family with the L9R mutation in the PDGFB gene.

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